Aging is associated with dysregulation of innate and adaptive immunity, which impairs an individual's ability to control infection by newly encountered pathogens. Aging also impacts neuroprotective mechanisms within the central nervous system (CNS), including the function of the blood-brain barrier (BBB), which limits the entry and replication of neutrotropic viruses. West Nile virus (WNV) is the leading cause of arthropod-transmitted viral infections in the United States. While most WNV infections are asymptomatic, individuals with symptomatic disease present either with a flu-like febrile illness that can progress to severe neuroinvasive diseases including meningitis, encephalitis, or flaccid paralysis. Severe WNV infection, especially fatal forms, predominate in the elderly. It is unclear whether this is due to effects of aging on viral invasion and/or virologic control within peripheral tissues or the CNS. To study many different aspects of immune regulation in adult mice, the Diamond and Klein laboratories have established a murine model of infection with a virulent WNV strain. However, interactions between antiviral immunity, neuroinflammation, and aging within the CNS have not been investigated. In this proposal, we will examine the impact of age on innate and adaptive immune mechanisms that control viral entry and clearance specifically within the CNS. The UH2 phase we will establish breeding cohorts and determine the feasibility of using 21 month-old aged animals in WNV infection studies. In the UH3 phase, we will explore how changes in skin immunity, BBB integrity, and CNS inflammation during aging influence neuroinvasion and disease progression associated with WNV infection.